Flumazenil is an antagonist of a benzodiazepine receptor of a brain, and benzodiazepine is a sedative-hypnotic drug that plays an important role in the central nervous system of the brain, and benzodiazepine has been used extensively in the medical field since 1960 and clinically used for treating anxiety disorder, insomnia, alcohol withdrawal syndrome, etc.
Gamma-Aminobutyric Acid (GABA) is recently discovered major inhibitory neurotransmitter capable of relieving or suppressing excessive excitement and intense nerve signal transmission to calm people down. GABA receptors are distributed extensively in cerebral cortex, and some of the GABA receptors have chloride ion channels, and these GABA receptors are benzodiazepine. The benzodiazepine receptors of this sort can be used for tracking a radioactive flumazenil derivative and pointing out the position of epilepsy more sensitively and accurately than [18F]FDG.
The so-called antagonist refers to a drug that can substitute benzodiazepine to combine with a receptor, so as to suppress related central nervous system activities of the bran and achieve a sedative, anticonvulsant or antiepileptic effect. The substitution simulates the active site of the benzodiazepine and provides a better affinity to enhance the structural basis of being the antagonist.
As to the structure of flumazenil, 1,4-benzodiazepine-2,5-dione acts as the basic structure, and this structure may be a benzodiazepine receptor antagonist, and thus it is a valuable research subject to produce a related derivative by a simple method and improve the performance by an appropriate structural modification.
In a conventional method of synthesizing a benzodiazepine derivative, isatoic anhydride and an amino acid are dissolved in dimethyl sulfoxide (DMSO) and then heated to perform a reaction and produce a crude product. After the crude product is pre-treated by neutralization and extraction, a column chromatography process is provided to elute and purify the crude product by ethyl acetate ethanol in an appropriate ratio, and finally a cyclized product is obtained.
However, the boiling point and polarity of DMSO are very high, so that the DMSO cannot be removed easily by simple evaporation or extraction, and a portion of DMSO together with the crude product goes through the column chromatography process. The quantity of the crude product increases with the DMSO, and thus the quantity of static phased filling becomes greater and the elution time becomes longer in the column chromatography process, and the chromatographed product is often an oily substance without a fixed shape. In the meantime, it is unable to find a suitable solvent for the re-crystallization to set the fixed shape of a solid. Regardless of the reaction conditions and the separation and purification methods, it is necessary to find a more appropriate process.
Therefore, it is a main technical issue for the present invention to provide a novel synthesis method to produce a benzodiazepine derivative in an easy and convenient manner and allow the structure to have a specific modification to increase the application value.